Background:Metronidazole is one of the first-line drugs of choice in the standard triple therapy used to eradicate Helicobacter pylori infection.Hence,the global emergence of metronidazole resistance in Hp poses a maj...Background:Metronidazole is one of the first-line drugs of choice in the standard triple therapy used to eradicate Helicobacter pylori infection.Hence,the global emergence of metronidazole resistance in Hp poses a major challenge to health professionals.Inactivation of RdxA is known to be a major mechanism of conferring metronidazole resistance in H.pylori.However,metronidazole resistance can also arise in H.pylori strains expressing functional RdxA protein,suggesting that there are other mechanisms that may confer resistance to this drug.Methods:We performed whole-genome sequencing on 121 H.pylori clinical strains,among which 73 were metronidazoleresistant.Sequence-alignment analysis of core protein clusters derived from clinical strains containing full-length RdxA was performed.Variable sites in each alignment were statistically compared between the resistant and susceptible groups to determine candidate genes along with their respective amino-acid changes that may account for the development of metronidazole resistance in H.pylori.Results:Resistance due to RdxA truncation was identified in 34%of metronidazole-resistant strains.Analysis of core protein clusters derived from the remaining 48 metronidazole-resistant strains and 48 metronidazole-susceptible identified four variable sites significantly associated with metronidazole resistance.These sites included R16H/C in RdxA,D85N in the inner-membrane protein RclC(HP0565),V265I in a biotin carboxylase protein(HP0370)and A51V/T in a putative threonylcarbamoyl–AMP synthase(HP0918).Conclusions:Our approach identified new potential mechanisms for metronidazole resistance in H.pylori that merit further investigation.展开更多
基金This project was supported by ShenZhen’s Sanming Project(Grant No:SZSM201510050)University of Malaya-Ministry of Education(UM-MoE)High Impact Research(HIR)grant(reference UM.C/625/1/HIR/MoE/CHAN13/3,Account No.H-50001-A000030)a National Health and Medical Research Council(NHMRC)Sir McFarlane Burnett Fellowship grant(572723)to B.J.M.,the Vice Chancellor of the University of Western Australia,and the Western Australian Department of Commerce and Department of Health.A.W.D.was supported by an Early Career Research Fellowship from the NHMRC(APP1073250).
文摘Background:Metronidazole is one of the first-line drugs of choice in the standard triple therapy used to eradicate Helicobacter pylori infection.Hence,the global emergence of metronidazole resistance in Hp poses a major challenge to health professionals.Inactivation of RdxA is known to be a major mechanism of conferring metronidazole resistance in H.pylori.However,metronidazole resistance can also arise in H.pylori strains expressing functional RdxA protein,suggesting that there are other mechanisms that may confer resistance to this drug.Methods:We performed whole-genome sequencing on 121 H.pylori clinical strains,among which 73 were metronidazoleresistant.Sequence-alignment analysis of core protein clusters derived from clinical strains containing full-length RdxA was performed.Variable sites in each alignment were statistically compared between the resistant and susceptible groups to determine candidate genes along with their respective amino-acid changes that may account for the development of metronidazole resistance in H.pylori.Results:Resistance due to RdxA truncation was identified in 34%of metronidazole-resistant strains.Analysis of core protein clusters derived from the remaining 48 metronidazole-resistant strains and 48 metronidazole-susceptible identified four variable sites significantly associated with metronidazole resistance.These sites included R16H/C in RdxA,D85N in the inner-membrane protein RclC(HP0565),V265I in a biotin carboxylase protein(HP0370)and A51V/T in a putative threonylcarbamoyl–AMP synthase(HP0918).Conclusions:Our approach identified new potential mechanisms for metronidazole resistance in H.pylori that merit further investigation.
